The interface between pharmacoepidemiology and pharmacogenetics

One of the most challenging areas of research in pharmacoepidemiology is to understand why individuals respond differently to drug therapy, both in terms of beneficial and adverse effects. Pharmacogenetics focuses on the question to what extent variability in genetic make-up is responsible for these observed differences. Pharmacoepidemiologic research can contribute to pharmacogenetics by explaining the observed variability in drug response in ‘real life’ patient populations with known polymorphisms in their genetic profile. Genetic pharmacoepidemiologists also are interested in the distribution of polymorphisms and correlated frequencies of responders and non-responders in the general population, and in searching for unknown genetic links to variability in drug response. In the future, we will probably have fewer drugs that suit all individuals. Genetic pharmacoepidemiology is going to play a major role in the development and evaluation of the concept of ‘tailor-made’ pharmacotherapy.     

斯巴敏与传统解痉剂治疗肠易激综合征的疗效对比

目的对照传统解痉剂观察斯巴敏治疗肠易激综合征(IBS)的疗效和安全性。方法选择本院消化内科符合IBS诊断的病人67例,随机分成二组,分别予以斯巴敏和654-2治疗,疗程均为2周,采取问卷调查、临床IBS症状疗效观察等方式。结果治疗2周后,斯巴敏组和654-2组的总有效率分别为76.2%和56%,两者比较有明显差异。结论斯巴敏不良反应小,是治疗IBS的一个有效的药物。     

斯巴敏与传统解痉剂治疗肠易激综合征的疗效对比

OBJECTIVE To check tradition spasmolytic and observe curative effect and safety of Spasmomen,Otilonium bromide for IBS treatment by contrast.METHODS To select 67 patients diagnosed IBS in the digest department of the hospital,divide them into 2 groups ran     

The role of metabonomics at the interface between drug metabolism and safety assessment

Safety assessment of candidate drugs is a key stage in drug development and one which represents a significant attritional hurdle. There is also a focused effort in drug metabolism studies to assess bioactivation potential based on the notion this could lead to the risk of macromolecule adduct formation and subsequent toxicological consequences. However, characterization of the molecular mechanisms of drug toxicity still remains an enormous challenge. Recent advancements in 'omics sciences, and in particular metabonomics, has enabled some elucidation or insights into toxicological sequelae. Metabonomics is a global metabolic profiling framework which utilizes high resolution analytics (typically NMR and mass spectrometry) together with chemometric statistical tools (such as principal component analysis and partial least squares) to derive an integrated picture of both endogenous and xenobiotic metabolism. This review details some of the current progress in the application of metabonomics in drug safety and metabolism.     

The pathogenic role of intestinal flora in IBD and colon cancer

The intestine is populated by a large variety of microorganisms that colonize the host soon after birth. The gut microflora contributes to several intestinal functions, including the development of the mucosal immune system, the absorption of complex macromolecules, the synthesis of amino acids and vitamins and the protection against pathogenic microorganisms. Its composition varies along the different segments of the gut, with a gradient from the stomach to the colon where it is more abundant. Given the vital relationship between the microflora and the intestinal function, it is important that the microflora is kept continuously under control so to preserve gut homeostasis. When this is not achieved or perturbed, several immune disorders can arise, like allergies or inflammation. Protracted immune deregulations can also lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). It is therefore crucial that the immune system learns both to tolerate and to control the growth of beneficial microorganisms so to preserve the intestinal homeostasis. The mechanisms that are in place to achieve this control are not yet understood but recent work has started to unravel the complex relationship between several players including the microflora, intestinal barriers and immune cells. In this review we will analyze how the microflora interacts with the host and how deregulation of this interaction can lead to inflammatory disorders and eventually also to cancer.     

IBD: immunologic research at The Mount Sinai Hospital

An evolution in our understanding of the inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, correlates with increased knowledge of the function of the mucosal immune system. In the early 1960s and 1970s, IBD was considered to be an autoimmune disease in which there was a directed attack by humoral and cellular elements of the immune system against intestinal tissues. These studies did not withstand the test of time, and from the 1970s through the 1990s there was a growing appreciation that defects in cellular immunity, not auto-reactive in nature, played a larger role in disease pathogenesis. Research at Mount Sinai focused in on these cellular T cell defects and helped pave the way for the current model of disease pathogenesis.     

The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention

Salmonella is a facultative intracellular pathogen that causes diseases ranging from self-limiting enteritis to typhoid fever. This bacterium uses two type III secretion systems to deliver effector proteins directly into the host cell to promote infection and disease. Recent characterization of these virulence proteins and their host-cell targets is uncovering the molecular mechanisms of Salmonella pathogenesis and is revealing a picture of the atomic interface between this pathogen and its host. This level of analysis provides the possibility of designing novel therapeutics to disrupt infection and disease processes at the molecular level.     

The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.     

Review of rifaximin as treatment for SIBO and IBS

Background: Rifaximin is a broad-range, gastrointestinal-specific antibiotic that demonstrates no clinically relevant bacterial resistance. Therefore, rifaximin may be useful in the treatment of gastrointestinal disorders associated with altered bacterial flora, including irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). Objective: To review rifaximin for treatment of IBS and SIBO. Methods: Review of rifaximin clinical trials. Results/conclusion: Rifaximin improved global symptoms in 33 – 92% of patients and eradicated SIBO in up to 84% of patients with IBS, with results sustained up to 10 weeks post-treatment. Rifaximin caused a lower number of adverse events compared with metronidazole or levofloxacin and may have a more favorable adverse event profile than systemic antibiotics, without clinically relevant antibiotic resistance.